Project Summary Traumatic brain injury (TBI) affects an estimated 1.7 million Americans a year and is the largest cause of disability-adjusted life years lost worldwide. Patients that survive TBIs will experience life-long impairments in physical, social, and cognitive functions. Despite this, care for TBI patients is palliative with no treatments to improve the long-term prognosis of patients. There is therefore an urgent need for new therapeutic technologies for the treatment of TBIs. In this application, I propose building new therapeutic materials exploiting the unique physical and biological properties that occur at the nanoscale. In particular, I believe that the damaged and dysregulated vasculature that is known to occur in TBI can be leveraged for access of nanoscale materials to the damaged brain. In this application, I hypothesize that it is possible to interact with the damaged vasculature in TBI on a molecular level and new ligands can be discovered in vivo phage library screening. I then lay out a strategy to incorporate these molecular approaches into nanoscale materials for two different therapeutic goals: (1) protection of the vulnerable neuronal population and/or regeneration of neuronal populations after TBI and (2) hasten the repair of the broken blood brain barrier after TBI to improve recovery. These therapeutic goals have different targets (neurons or endothelium) and are complementary approaches to improving the prognosis of TBI patients. This application is suitable for the New Innovator Award program because it has the potential to have high impact on the treatment of TBI, which has few therapeutic options. It furthermore has the potential to have a broader impact on central nervous system diseases as a whole, since there is evidence that a dysregulated vasculature is present in many neurodegenerative diseases. The major innovation of the application is to apply technologies and concepts learned from the field of cancer nanomedicine, which has been an area of active research for the past 20 years, to the challenges presented in TBI, to which nanomedicine has yet to be applied to in significant levels. I believe this approach high potential to yield significant advancement in therapeutics and understanding of TBI.